Search

The emission of CO2 is a significant contributor to global warming, with the mobility sector being a major source. The EU has set a goal to achieve climate neutrality by 2050, requiring substantial CO2 reduction efforts, particularly in densely populated regions like the Rhine-Delta (RDR). This region’s extensive mobility network, serving both urban and global trade needs, generates significant CO2 emissions. To address this, a research initiative aims to make the Rhine-Delta’s mobility network CO2-neutral by 2050 through reimagining its design and operations. The focus lies on peri-urban areas, where urban and rural landscapes intersect. These areas are essential for economic and social functions but are currently reliant on polluting road transportation. The research identifies the need to rethink connectivity to peri-urban areas for sustainability. Traditional urban-focused transportation concepts often overlook peri-urban needs. Therefore, the initiative proposes developing context-based mobility nodes tailored to peri-urban requirements. These nodes aim to promote sustainable transportation and enhance network efficiency. The approach involves creating an interconnected network of such nodes throughout the Rhine-Delta region, addressing the specific needs of lower-density areas like peri-urban zones. By considering local contexts, these nodes can effectively serve peri-urban areas, promoting sustainable transportation practices. To demonstrate the feasibility of this approach, the research zooms in on a representative area within the Rhine-Delta region, focusing on peri-urban patches around Arnhem-Nijmegen. By showcasing how context-based mobility nodes can be implemented in such areas, the research seeks to pave the way for a broader transition towards a CO2-neutral mobility network by 2050. In conclusion, the research aims to transform the Rhine-Delta’s mobility landscape by making it CO2-neutral through the implementation of sustainable, AR2U086 R&D Studio – Spatial Strategies for the Global Metropolis, Architecture, Urbanism and Building Sciences | Urbanism

The increasing size of deep neural networks necessitates effective model compression to improve computational efficiency and reduce their memory footprint. Sparsity and quantization are two prominent compression methods that have individually demonstrated significant reduction in computational and memory footprints while preserving model accuracy. While effective, the interplay between these two methods remains an open question. In this paper, we investigate the interaction between these two methods and assess whether their combination impacts final model accuracy. We mathematically prove that applying sparsity before quantization is the optimal sequence for these operations, minimizing error in computation. Our empirical studies across a wide range of models, including OPT and Llama model families (125M-8B) and ViT corroborate these theoretical findings. In addition, through rigorous analysis, we demonstrate that sparsity and quantization are not orthogonal; their interaction can significantly harm model accuracy, with quantization error playing a dominant role in this degradation. Our findings extend to the efficient deployment of large models in resource-limited compute platforms and reduce serving cost, offering insights into best practices for applying these compression methods to maximize efficacy without compromising accuracy.

Bu kitapçık çocuk yanıkları ile karşılaşan pratisyen hekimler ve diğer sağlık profesyonelleri için güncel tedavi protokollerinin özetlendiği bir kaynak olarak hazırlanmıştır. Kendine has özellikleri nedeniyle yanık yarasının patofizyolojisinin bilinmesi yanık yarasına yaklaşımda neyin neden yapılması gerektiğinin anlaşılmasını sağlayacaktır. Sağlıklı derinin yapısı ile yanık yarasının iyileşme aşamalarının detaylandırıldığı bölümlerde temel anatomik ve histolojik bilgiler özetlenmiştir. Bunun yanı sıra yanık hastasına ve yanık yarasına yaklaşımda çocuk yanıklarını erişkin yanıklarının küçüğü olarak değerlendirme hatasına düşülmemesi için dikkat edilmesi gereken hususlar üzerinde durulmuştur., This booklet has been prepared as a resource that summarizes current treatment protocols for general practitioners and other health professionals who encounter child burns. Knowing the pathophysiology of the burn wound due to its unique characteristics will allow to understand what should be done and why in the approach to the burn wound. Basic anatomical and histological information are summarized in the sections where the structure of healthy skin and the healing stages of the burn wound are detailed. In addition, in the approach to the burn patient and burn wound, the points to be considered in order not to make the mistake of considering child burns as the smallest of adult burns have been emphasized.

Chromosomal rearrangements are important drivers in cancer, and their robust detection is essential for diagnosis, prognosis, and treatment selection, particularly for bone and soft tissue tumors. Current diagnostic methods are hindered by limitations, including difficulties with multiplexing targets and poor quality of RNA. A novel targeted DNA-based next-generation sequencing method, formalin-fixed, paraffin-embedded-targeted locus capture (FFPE-TLC), has shown advantages over current diagnostic methods when applied on FFPE lymphomas, including the ability to detect novel rearrangements. We evaluated the utility of FFPE-TLC in bone and soft tissue tumor diagnostics. FFPE-TLC sequencing was successfully applied on noncalcified and decalcified FFPE samples (n = 44) and control samples (n = 19). In total, 58 rearrangements were identified in 40 FFPE tumor samples, including three previously negative samples, and none was identified in the FFPE control samples. In all five discordant cases, FFPE-TLC could identify gene fusions where other methods had failed due to either detection limits or poor sample quality. FFPE-TLC achieved a high specificity and sensitivity (no false positives and negatives). These results indicate that FFPE-TLC is applicable in cancer diagnostics to simultaneously analyze many genes for their involvement in gene fusions. Similar to the observation in lymphomas, FFPE-TLC is a good DNA-based alternative to the conventional methods for detection of rearrangements in bone and soft tissue tumors.

BACKGROUND Liquid biopsies combine minimally invasive sample collection with sensitive detection of residual disease. Pediatric malignancies harbor tumor-driving copy number alterations or fusion genes, rather than recurrent point mutations. These regions contain tumor-specific DNA breakpoint sequences. We investigated the feasibility to use these breakpoints to design patient-specific markers to detect tumor-derived cell-free DNA (cfDNA) in plasma from patients with pediatric solid tumors. MATERIALS AND METHODS Regions of interest (ROI) were identified through standard clinical diagnostic pipelines, using SNP array for CNAs, and FISH or RT-qPCR for fusion genes. Using targeted locus amplification (TLA) on tumor organoids grown from tumor material or targeted locus capture (TLC) on FFPE material, ROI-specific primers and probes were designed, which were used to design droplet digital PCR (ddPCR) assays. cfDNA from patient plasma at diagnosis and during therapy was analyzed. RESULTS TLA was performed on material from 2 rhabdomyosarcoma, 1 Ewing sarcoma and 3 neuroblastoma. FFPE-TLC was performed on 8 neuroblastoma tumors. For all patients, at least one patient-specific ddPCR was successfully designed and in all diagnostic plasma samples the patient-specific markers were detected. In the rhabdomyosarcoma and Ewing sarcoma patients, all samples after start of therapy were negative. In neuroblastoma patients, presence of patient-specific markers in cfDNA tracked tumor burden, decreasing during induction therapy, disappearing at complete remission and re-appearing at relapse. CONCLUSION We demonstrate the feasibility to determine tumor-specific breakpoints using TLA/TLC in different pediatric solid tumors and use these for analysis of cfDNA from plasma. Considering the high prevalence of CNAs and fusion genes in pediatric solid tumors, this approach holds great promise and deserves further study in a larger cohort with standardized plasma sampling protocols.

Penelitian ini bertujuan untuk mengetahui tingkat kepuasan pelanggan yang diberikan oleh Shopee kepada konsumennya. Penelitian ini menggunakan 5 dimensi kualitas pelayanan untuk mengetahui tingkat kepuasan pelanggan berdasarkan bukti langsung (tangible), keandalan (reability), daya tanggap (responsiveness), jaminan (assurance), dan kepedulian (empathy). Dalam penelitian ini dapat didefenisikan permasalahan yang terjadi seperti banyaknya pesaing yang menawarkan produk-produk sejenis, terdapat beberapa hal mengenai ketidakpuasan konsumen dari dimendsi bukti langsung (tangible), keandalan (reability), daya tanggap (responsiveness), jaminan (assurance), , dan kepedulian (empathy). Batasan dalam penelitian ini hanya pada analisis kepuasan pelanggan terhadap pelayanan situs online shop Shopee. Teknik pengumpulan data yang digunakan dalam penelitian ini yaitu dengan menggunakan angket, sedangkan analisis data yang dilakukan menggunakan teknik Analisis Importance Performace. Adapun hasil dari penelitian ini yaitu masih terdapat beberapa pelanggan yang merasa kurang puas dengan pelayanan yang diberikan oleh Shopee berdasarkan 5 dimensi kualitas pelayanan pada bukti langsung (tangible), keandalan (reability), daya tanggap (responsiveness), jaminan (assurance), dan kepedulian (empathy).

The change score on a test or questionnaire that represents an important improvement or deterioration for a patient, is referred to as the minimal clinically important difference (MCID). MCIDs are a mandatory lower limit for the approval and evaluation of new treatments. It is therefore very important that correct MCIDs are determined. In this thesis, the MCIDs of several questionnaires were calculated, compared with each other and investigated for factors influencing this measurement. The study was conducted in people with chronic obstructive pulmonary disease (COPD) with the three main health status questionnaires. Data were collected from (1) a literature review; (2) a clinical study in a German pulmonary rehabilitation clinic; and (3) a questionnaire study in Dutch COPD patients treated by their general practitioner and/or pulmonary physician. Small differences were observed for the questionnaire MCIDs between multiple approaches used and during various follow-up periods. Despite minor differences, the MCIDs for people with an improved health status were found to be fairly similar to those for people with an experienced deterioration. Furthermore, the MCIDs for patients in the German pulmonary rehabilitation study were higher than for Dutch routine care patients. Moreover, a larger relevant improvement in health status (a higher MCID) was noted for patients, who already had many symptoms and limitations at the start of the study. This was similar for women, participants aged 60 years or over, patients with a good lung function, and people with fewer co-morbid diseases. However, these patient groups needed only little additional deterioration in health status (a lower MCID) to actually feel worse.

More often associated with hedonism and cheap thrills than with notions of alienation and suffering, Beat literature has rarely been envisaged from the perspective of the paradoxical dynamics at play in the writings. What this book evidences is that the sacrosanct quest for transcendence staged by Kerouac and by Ginsberg is underpinned, primarily, by a trope of nullification that acts as a menace for the self. This tropism for destruction and death is not only emblematic of their works, it is also used as a literary strategy that seeks to conquer the fear of self-annihilation through the writing itself. It is precisely this interplay—approached through an Existentialism that simultaneously converges upon the Transcendentalist legacy of Beat writing—which probes the paradoxical dimension of the texts, enabling the mythological figure of Thanatos to take centre stage. The critical synergy of the book, brought about by relating American literature and culture to European thought, enables in-depth analyses of a selection of novels and poems, grasped through their aesthetic, ontological and historical dimensions. Shedding new light on the literary strategies of two widely misunderstood American writers of the twentieth century, this captivating study into the drives for self-destruction and self-liberation encapsulated by Kerouac and Ginsberg sets out to reinvent the well-worn definition of ‘Beat’ through its original approach—an essential critical piece for all those interested in the American counterculture.

The unprecedented demand for computing resources to train DNN models has led to a search for minimal numerical encoding. Recent state-of-the-art (SOTA) proposals advocate for multi-level scaled narrow bitwidth numerical formats. In this paper, we show that single-level scaling is sufficient to maintain training accuracy while maximizing arithmetic density. We identify a previously proposed single-level scaled format for 8-bit training, Hybrid Block Floating Point (HBFP), as the optimal candidate to minimize. We perform a full-scale exploration of the HBFP design space using mathematical tools to study the interplay among various parameters and identify opportunities for even smaller encodings across layers and epochs. Based on our findings, we propose Accuracy Booster, a mixed-mantissa HBFP technique that uses 4-bit mantissas for over 99% of all arithmetic operations in training and 6-bit mantissas only in the last epoch and first/last layers. We show Accuracy Booster enables increasing arithmetic density over all other SOTA formats by at least 2.3x while achieving state-of-the-art accuracies in 4-bit training.

Minimal residual disease (MRD) diagnostics are implemented in most clinical protocols for patients with acute lymphoblastic leukaemia (ALL) and are mostly performed using rearranged immunoglobulin (IG) and/or T-cell receptor (TR) gene rearrangements as molecular polymerase chain reaction targets. Unfortunately, in 5–10% of patients no or no sensitive IG/TR targets are available, and patients therefore cannot be stratified appropriately. In the present study, we used fusion genes and genomic deletions as alternative MRD targets in these patients, which retrospectively revealed appropriate MDR stratification in 79% of patients with no (sensitive) IG/TR target, and a different risk group stratification in more than half of the cases.

In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.

Contains fulltext : 236734.pdf (Publisher’s version ) (Open Access)

Minimal residual disease (MRD) diagnostics are implemented in most clinical protocols for patients with acute lymphoblastic leukaemia (ALL) and are mostly performed using rearranged immunoglobulin (IG) and/or T-cell receptor (TR) gene rearrangements as molecular polymerase chain reaction targets. Unfortunately, in 5–10% of patients no or no sensitive IG/TR targets are available, and patients therefore cannot be stratified appropriately. In the present study, we used fusion genes and genomic deletions as alternative MRD targets in these patients, which retrospectively revealed appropriate MDR stratification in 79% of patients with no (sensitive) IG/TR target, and a different risk group stratification in more than half of the cases.

‘Ouder worden komt met gebreken’. Met andere woorden: Met de leeftijd neemt het aantal comorbiditeiten en chronische condities toe. Met het stijgen van de levensverwachting kunnen we daarom verwachten dat het aantal ouderen dat gespecialiseerde geriatrische zorg nodig heeft ook zal stijgen. Geriaters richten zich op deze kwetsbare populatie, en hebben als doel om ziektes te behandelen en functies van het dagelijks leven zoveel mogelijk te behouden. Cognitieve achteruitgang (zoals vormen van dementie of milde cognitieve problematiek (MCI)) heeft een desastreus e ect op het dagelijks functioneren van ouderen. Ondanks dat medische behandelingen cognitieve achteruitgang nog niet kunnen ‘genezen’, blijken doelgerichte interventies het ziekteproces wel te vertragen. Omdat er een duidelijk verband is aangetoond tussen motorisch- en cognitief functioneren in verschillende takken van wetenschappelijk onderzoek (e.g., neurowetenschappen en gedragswetenschappen), veronderstelt het huidige proefschrift dat karakteristieken van het lopen kunnen dienen als non-invasieve indicatoren van cognitieve achteruitgang in geriatrische patiënten. Het overkoepelende doel van dit proefschrift was daarom om meer inzicht te verkrijgen in de relatie tussen lopen en cognitie in geriatrische patiënten, waarbij een breed scala aan loopvariabelen is berekend uit 3D-acceleraties van de onderrug (gerelateerd aan loopsnelheid en de dynamica van het lopen). De ‘Loss of Complexity’ hypothese heeft gefungeerd als theoretisch kader. Multivariate analyses zijn vervolgens gebruikt om loopvariabelen te relateren aan cognitieve- en val-status., The rising life expectancy will result in an increased number of ‘older old adults’ who will need specialized geriatric care to slow functional decline. Cognitive impairment is a major cause of disability in geriatric patients. Even though there is no cure yet to reverse neurodegeneration, tailored interventions can slow disease progression and reduce symptoms. Because of the abundant evidence from experimental, neuroscienti c, and behavioral studies that underscored the close link between motor- and cognitive function, the present thesis proposed to use gait characteristics as non-invasive indicators of cognitive impairment and falls in geriatric patients. The main objective therefore was to increase our understanding of the relationship between gait and cognition in this vulnerable population, in which gait outcomes were calculated from 3D-acceleration signals of the lower trunk that were collected with an iPod Touch 4G. The ‘Loss of Complexity’ hypothesis provided a theoretical framework. Multivariate analyses were applied to dynamic gait outcomes in relation to cognitive- and fall-status.

Interspeech 2020, 25 oktober 2020, Contains fulltext : 228158.pdf (publisher's version ) (Open Access)

We live in the technology era and over the last decade Artificial Intelligence (AI) has been the most focused technology. It has applications in countless topics and neural machine translation (NMT) is one of the major research areas. Many big companies like Google, Facebook, Amazon, Microsoft, Yandex deploy NMT in their production systems and NMT services has become popular lately. These services need to provide some constraints, especially speed and translation quality, for user satisfaction. There has been significant amount of work on accelerating NMT models however to the best of our knowledge, there is no detailed research giving a detailed performance analysis of each step in a model. In this work, one of the state-of-the-art models the Transformer is used. It has encoder-decoder architecture with an additional attention mechanism. A microservice is implemented on top of the Transformer model and it is showed that the bottleneck is the model itself. Then, several experiments with different configuration values has been conducted and it is observed that the performance of the model is highly sensitive to the changes in these values. A detailed performance breakdown of the model in CPU and GPU show that beam search is a big source of inefficiency. So a detailed time breakdown of the beam search is obtained in order to have a better understanding. Additionally, it is observed that the beam size only affects BLEU score at word level, and not at token level. Finally, it is showed that the vocabulary size has a major role on the performance of the beam search., Teknoloji çağında yaşıyoruz ve son on yılda Yapay Zeka üzerine en çok çalışılan teknoloji olmuştur. Sayısız alanda uygulaması bulunmakla birlikte, Yapay Sinir Ağları ile Makine Çevirisi (YMÇ) temel araştırma alanlarından birisidir. Google, Facebook, Amazon, Microsoft, Yandex gibi birçok büyük şirket ürünlerinde YMÇ kullanmaktadır ve YMÇ'nin kullanıcılara servis olarak sunulması son zamanlarda benimsenen bir yöntem olmuştur. Bu servislerin, kullanıcı memnuniyeti açısından, hız ve çeviri kalitesi başta olmak üzere bazı kısıtları sağlamaları gerekmektedir. YMÇ modellerini hızlandır- mak konusunda birçok çalışma yapılmıştır, ancak bildiğimiz kadarıyla bu çalışmaların hiçbiri detaylı başarım/zaman analizinde bulunmamıştır. Bu çalışmada en gelişmiş YMÇ modellerinden birisi olan, kodlayıcı-kodçözücü yapısını ilgi mekanizmasıyla birleştiren Dönüştürücü modeli ile çalışılmıştır. Dönüştürücü'nün etrafına bir mikroservis kurulmuş ve sistemin darboğazının modelin kendisi olduğu gösterilmiştir. Bunun üzerine temel yapılandırma parametrelerinin değişimiyle deneyler yapılmış ve bu parametrelerin başarımı hassas bir şekilde etkilediği gözlenmiştir. Bunun üzerine modelin her bir bileşeninin CPU ve GPU'da detaylı zaman dökümü çıkarılmış ve en verimsiz aşamanın ışın araması olduğu gösterilmiştir. Daha sonra ışın aramasının daha iyi anlaşılması adına her bir adımını gösteren zaman dökümü çıkarılmıştır. Ayrıca, ışın boyutunun BLEU skorunu sadece kelime-bazında etkilediği, türce-bazında bir etkisinin olmadığı gözlemlenmiştir. Son olarak kelime-hazinesi büyüklüğünün ışın aramasının başarımında büyük rolü olduğu gösterilmiştir.

The KRAS gene is highly mutated in human cancers and the focus of current Ras drug development efforts. Recently the interface between the C-terminus of K-Ras and calmodulin (CaM) was proposed as a target site to block K-Ras driven cancer cell stemness. We therefore aimed at developing a high-throughput amenable screening assay to identify novel CaM-inhibitors as potential K-Ras stemness-signaling disruptors. A modulated time-resolved Förster resonance energy transfer (mTR-FRET)-assay was developed and benchmarked against an identically designed fluorescence anisotropy (FA)-assay. In both assays, two CaM-binding peptides were labeled with Eu(III)-chelate or fluorescein and used as single-label reporter probes that were displaced from CaM upon competitor binding. Thus, peptidic and small molecule competitors with nanomolar to micromolar affinities to CaM could be detected, including a peptide that was derived from the C-terminus of K-Ras. In order to detect CaM-residue specific covalent inhibitors, a cell lysate-based Förster resonance energy transfer (FRET)-assay was furthermore established. This assay enabled us to measure the slow, residue-specific, covalent inhibition by ophiobolin A in the presence of other endogenous proteins. In conclusion, we have developed a panel of fluorescence-assays that allows identification of conventional and covalent CaM-inhibitors as potential disruptors of K-Ras driven cancer cell stemness.

ObjectivePrior functional magnetic resonance imaging (fMRI) work has revealed that children/adolescents with disruptive behavior disorders (DBDs) show dysfunctional reward/non-reward processing of non-social reinforcements in the context of instrumental learning tasks. Neural responsiveness to social reinforcements during instrumental learning, despite the importance of this for socialization, has not yet been previously investigated.MethodsTwenty-nine healthy children/adolescents and 19 children/adolescents with DBDs performed the fMRI social/non-social reinforcement learning task. Participants responded to random fractal image stimuli and received social and non-social rewards/non-rewards according to their accuracy.ResultsChildren/adolescents with DBDs showed significantly reduced responses within the caudate and posterior cingulate cortex (PCC) to non-social (financial) rewards and social non-rewards (the distress of others). Connectivity analyses revealed that children/adolescents with DBDs have decreased positive functional connectivity between the ventral striatum (VST) and the ventromedial prefrontal cortex (vmPFC) seeds and the lateral frontal cortex in response to reward relative to non-reward, irrespective of its sociality. In addition, they showed decreased positive connectivity between the vmPFC seed and the amygdala in response to non-reward relative to reward.ConclusionThese data indicate compromised reinforcement processing of both non-social rewards and social non-rewards in children/adolescents with DBDs within core regions for instrumental learning and reinforcement-based decision- making (caudate and PCC). In addition, children/adolescents with DBDs show dysfunctional interactions between the VST, vmPFC, and lateral frontal cortex in response to rewarded instrumental actions potentially reflecting disruptions in attention to rewarded stimuli.

Telah dilakukan karakterisasi arus dan tegangan sensor gas oksigen berbentuk pelet dari bahan semikonduktor TiO2 didoping dengan SnO2. Sensor gas oksigen dibuat dengan konsentrasi doping SnO2 berbeda. Sensor gas oksigen diawali dengan pencampuran bahan, kemudian sampel dikalsinasi pada temperatur 500 °C selama 4 jam, penggerusan, kompaksi dan sintering pada temperatur 700 °C selama 4 jam mengunakan metode reaksi dalam keadaan padat. Sensor gas oksigen diuji pada temperatur ruang untuk mendapatkan karakteristik I-V, menghitung nilai sensitivitas, konduktivitas, waktu respon dan karakterisasi XRD. Berdasarkan pengukuran karakteristik I-V, sensitivitas tertinggi terdapat pada sampel 92% mol TiO2+ 8% mol SnO2 yaitu 4,08 pada tegangan 24 volt. Nilai konduktivitas tertinggi dimiliki sampel 92% mol TiO2 + 8% mol SnO2 yaitu 2,81 x 10-2/Ωm pada lingkungan oksigen. Waktu respon sampel 92% mol TiO2 + 8 % mol SnO2 pada tegangan 24 volt adalah 39 sekon. Hasil XRD menunjukan ukuran kristal 92% mol TiO2 + 8 % mol SnO2 yaitu 86,53 nm, lebih kecil dibandingkan dengan TiO2 murni yaitu 121,17 nm. Kata Kunci : Sensor gas oksigen, TiO2-SnO2, sensitivitas, konduktivitas, waktu respon.

Performance of dairy cows can be influenced by early life nutrient supply. Adipose tissue is diet sensitive and an important component in that process as it is involved in the regulation of energetic, reproductive and immunological functions. However, it is not clear how early life nutrition alters the molecular regulation of adipose tissue in calves and potentially adult individuals. This study aimed at determining how differences in pre-weaning nutrient supply alter gene expression profiles and physiology in omental adipose tissue. A total of 12 female Holstein calves were fed two levels of milk replacer supply: a restricted amount of 11.72 MJ of metabolizable energy (ME) intake per day (n = 6) or an enhanced amount of 1.26 MJ ME intake per kg of metabolic body weight (BW0.75), resulting in supply from 17.58 to 35.17 MJ ME intake per day (n = 6). All calves had ad libitum access to a commercial calf starter and water. Analysis of the transcriptome profiles at 54 ± 2 days of age revealed that a total of 396 out of 19,968 genes were differentially expressed (DE) between groups (p < 0.001, FDR < 0.1). The directional expression of DE genes through Ingenuity Pathway Analysis showed that an enhanced nutrient supply alters adipose tissue physiology of pre-weaned calves. Several biological functions were increased (Z-score > +2), including Lipid Metabolism (Fatty Acid Metabolism), Cell Cycle (Entry into Interphase, Interphase, Mitosis and Cell Cycle Progression), Cellular Assembly and Organization (Cytoskeleton Formation and Cytoplasm Development) and Molecular Transport (Transport of Carboxylic Acid). These changes were potentially orchestrated by the activation/inhibition of 17 upstream regulators genes. Our findings indicate that adipose tissue of calves under an enhanced nutrient supply is physiologically distinct from restricted calves due to an increased development/expansion rate and also a higher metabolic activity through increased fatty acid metabolism.

ObjectiveIn the current study we investigated neurodevelopmental changes in response to social and non-social reinforcement.MethodsFifty-three healthy participants including 16 early adolescents (age, 10-15 years), 16 late adolescents (age, 15-18 years), and 21 young adults (age, 21-25 years) completed a social/non-social reward learning task while undergoing functional magnetic resonance imaging. Participants responded to fractal image stimuli and received social or non-social reward/non-rewards according to their accuracy. ANOVAs were conducted on both the blood oxygen level dependent response data and the product of a context-dependent psychophysiological interaction (gPPI) analysis involving ventromedial prefrontal cortex (vmPFC) and bilateral insula cortices as seed regions.ResultsEarly adolescents showed significantly increased activation in the amygdala and anterior insula cortex in response to non-social monetary rewards relative to both social reward/non-reward and monetary non-rewards compared to late adolescents and young adults. In addition, early adolescents showed significantly more positive connectivity between the vmPFC/bilateral insula cortices seeds and other regions implicated in reinforcement processing (the amygdala, posterior cingulate cortex, insula cortex, and lentiform nucleus) in response to non-reward and especially social non-reward, compared to late adolescents and young adults.ConclusionIt appears that early adolescence may be marked by: (i) a selective increase in responsiveness to non-social, relative to social, rewards; and (ii) enhanced, integrated functioning of reinforcement circuitry for non-reward, and in particular, with respect to posterior cingulate and insula cortices, for social non-reward.

Study Objectives: Tolerance to shift work varies; only some shift workers suffer from disturbed sleep, fatigue, and job-related exhaustion. Our aim was to explore molecular genetic risk factors for intolerance to shift work. Methods: We assessed intolerance to shift work with job-related exhaustion symptoms in shift workers using the emotional exhaustion subscale of the Maslach Burnout Inventory-General Survey, and carried out a genome-wide association study (GWAS) using Illumina's Human610-Quad BeadChip (n = 176). The most significant findings were further studied in three groups of Finnish shift workers (n = 577). We assessed methylation in blood cells with the Illumina HumanMethylation450K BeadChip, and examined gene expression levels in the publicly available eGWAS Mayo data. Results: The second strongest signal identified in the GWAS (p = 2.3 x 10E-6) was replicated in two of the replication studies with p Conclusions: These findings suggest that a variant near MTNR1A may be associated with job-related exhaustion in shift workers. The risk variant may exert its effect via epigenetic mechanisms, potentially leading to reduced melatonin signaling in the brain. These results could indicate a link between melatonin signaling, a key circadian regulatory mechanism, and tolerance to shift work.

Om interacties met anderen goed te laten verlopen, is het belangrijk dat we begrijpen wat zij doen en ervaren. Uit onderzoek is gebleken dat een van de mogelijke mechanismen hierachter ligt in het ‘heractiveren’van hersengebieden - die we gebruiken om acties uit te voeren en emoties en aanrakingen te ervaren - wanneer we anderen waarnemen die deze handelingen uitvoeren of emoties en aanrakingen ervaren. Deze ‘heractivatie’ van hersengebieden zou ons een soort privé ervaring van het gevoel van een ander kunnen geven. Neem als voorbeeld van de pijn die we zelf voelen, wanneer we iemand anders zien die zich in de vinger snijdt. In dit proefschrift onderzochten we het neurale mechanisme dat hieraan ten grondslag ligt bij een groep mensen gediagnosticeerd met psychopathie. Een belangrijk kenmerk van deze mentale stoornis is het verminderd vermogen om mee te voelen met de emoties van anderen en deze te herkennen. Wij hebben in dit onderzoek bekeken of dit samenhangt met een vermindere activatie van de hersengebieden voor emoties, acties en sensaties, wanneer mensen met psychopathie kijken naar andere mensen die iets meemaken. De resultaten van dit proefschrift suggereren dat psychopathie niet zozeer een onvermogen is om deze gebieden te activeren, maar wel dat zij dit spontaan minder sterk doen. Aangezien het de eerste keer is dat soortgelijk onderzoek is uitgevoerd bij deze doelgroep, zullen de resultaten nog moeten worden geverifieerd in vervolgonderzoek. Deze informatie zou dan mogelijk kunnen leiden tot alternatieve therapeutische strategieën.

Beleid bij ziekteverzuim richt zich vaak op langdurig zieken. Jolanda Schreuder stelt dat organisaties en bedrijven er goed aan doen om meer aandacht te schenken aan medewerkers die regelmatig kortdurend ziek zijn, en medewerkers die nooit afwezig zijn. Deze laatste groep, de nulverzuimers, zijn binnen een team belangrijke ondersteuners van de leidinggevende maar worden vaak niet voldoende op waarde geschat. Kortdurend verzuim heeft een relatie met gedrag, beïnvloedt direct het werkproces en leidt tot onderbezetting. Daarnaast lopen werknemers die regelmatig kort verzuimen, het risico op toekomstig langdurig verzuim. Nulverzuimers komen dezelfde problemen in het werk tegen, worden aangestuurd door dezelfde leidinggevenden en vallen onder hetzelfde organisatiebeleid. Ondanks dat veel organisaties veel moeite doen om het ziekteverzuim te managen, worden nulverzuimers meestal niet opgemerkt. Schreuder verrichtte haar onderzoek in Ziekenhuis Nij Smellinghe te Drachten. In dit ziekenhuis vormt het managen van ziekteverzuim een belangrijk onderdeel van het organisatiebeleid. Het resultaat hiervan was het behalen van de laagste verzuimcijfers in 2010 voor de branche Algemene Ziekenhuizen, gemeten door Vernet, de marktleider in benchmark voor de gezondheidszorg in Nederland. De bevindingen leveren extra kennis over ziekteverzuimmanagement en geven praktische hulpmiddelen ter verbetering ervan. Het managen van ziekteverzuim vraagt een doelgerichte aanpak met maatwerk per werknemer. Daarin spelen niet alleen de werknemer, de leidinggevende en de bedrijfsarts een belangrijke rol, maar ook het team waarin de werknemer werkt. De resultaten van dit proefschrift rechtvaardigen meer aandacht voor kortdurend ziekteverzuim, nulverzuim en ‘psychological capital’van individuele werknemers en teams.

Ioanna G Tsiligianni,1,2 Harma J Alma,1,2 Corina de Jong,1,2 Danijel Jelusic,3 Michael Wittmann,3 Michael Schuler,4 Konrad Schultz,3 Boudewijn J Kollen,1 Thys van der Molen,1,2 Janwillem WH Kocks1,2 1Department of General Practice, 2GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 3Klinik Bad Reichenhall, Center for Rehabilitation, Pulmonology and Orthopedics, Bad Reichenhall, 4Department of Medical Psychology, Psychotherapy and Rehabilitation Sciences, University of Würzburg, Würzburg, Germany Background: In the GOLD (Global initiative for chronic Obstructive Lung Disease) strategy document, the Clinical COPD Questionnaire (CCQ), COPD Assessment Test (CAT), or modified Medical Research Council (mMRC) scale are recommended for the assessment of symptoms using the cutoff points of CCQ ≥1, CAT ≥10, and mMRC scale ≥2 to indicate symptomatic patients. The current study investigates the criterion validity of the CCQ, CAT and mMRC scale based on a reference cutoff point of St George’s Respiratory Questionnaire (SGRQ) ≥25, as suggested by GOLD, following sensitivity and specificity analysis. In addition, areas under the curve (AUCs) of the CCQ, CAT, and mMRC scale were compared using two SGRQ cutoff points (≥25 and ≥20).Materials and methods: Two data sets were used: study A, 238 patients from a pulmonary rehabilitation program; and study B, 101 patients from primary care. Receiver-operating characteristic (ROC) curves were used to assess the correspondence between the recommended cutoff points of the questionnaires.Results: Sensitivity, specificity, and AUC scores for cutoff point SGRQ ≥25 were: study A, 0.99, 0.43, and 0.96 for CCQ ≥1, 0.92, 0.48, and 0.89 for CAT ≥10, and 0.68, 0.91, and 0.91 for mMRC ≥2; study B, 0.87, 0.77, and 0.9 for CCQ ≥1, 0.76, 0.73, and 0.82 for CAT ≥10, and 0.

Degeneration of nigrostriatal dopaminergic system is the principal lesion in Parkinson's disease. Because glial cell line-derived neurotrophic factor (GDNF) promotes survival of dopamine neurons in vitro and in vivo, intracranial delivery of GDNF has been attempted for Parkinson's disease treatment but with variable success. For improving GDNF-based therapies, knowledge on physiological role of endogenous GDNF at the sites of its expression is important. However, due to limitations of existing genetic model systems, such knowledge is scarce. Here, we report that prevention of transcription of Gdnf 3'UTR in Gdnf endogenous locus yields GDNF hypermorphic mice with increased, but spatially unchanged GDNF expression, enabling analysis of postnatal GDNF function. We found that increased level of GDNF in the central nervous system increases the number of adult dopamine neurons in the substantia nigra pars compacta and the number of dopaminergic terminals in the dorsal striatum. At the functional level, GDNF levels increased striatal tissue dopamine levels and augmented striatal dopamine release and re-uptake. In a proteasome inhibitor lactacystin-induced model of Parkinson's disease GDNF hypermorphic mice were protected from the reduction in striatal dopamine and failure of dopaminergic system function. Importantly, adverse phenotypic effects associated with spatially unregulated GDNF applications were not observed. Enhanced GDNF levels up-regulated striatal dopamine transporter activity by at least five fold resulting in enhanced susceptibility to 6-OHDA, a toxin transported into dopamine neurons by DAT. Further, we report how GDNF levels regulate kidney development and identify microRNAs miR-9, miR-96, miR-133, and miR-146a as negative regulators of GDNF expression via interaction with Gdnf 3'UTR in vitro. Our results reveal the role of GDNF in nigrostriatal dopamine system postnatal development and adult function, and highlight the importance of correct spatial express

Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer.

Previous work has documented that attachment security is systematically linked with child adjustment and academic competence. This study aims to examine the associations between parents' own report of anxious and avoidant attachment and their children's report of trait anxiety and academic self-efficacy in math and Turkish literature courses. Mothers (N=1539) and fathers (N=1436) from four cities in Turkey, separately completed the measures of attachment orientations, and their children (N=1877), attending 4th and 5th grades, completed the measures of trait anxiety and academic self-concept on math and literature courses in their school. Regression analyses showed that whereas mother attachment anxiety predicted boys' trait anxiety, father attachment avoidance predicted girls' anxiety. In predicting academic self-efficacy, mother attachment avoidance predicted their son's and father attachment anxiety predicted their daughter's academic self-efficacy in both math and literature courses. Our results confirmed the importance of having a warm and secure romantic attachment between spouses in marriage, not only for their relationship satisfaction and happiness, but also for their children's emotional adjustment and academic competence., El trabajo anterior documentó que el apego seguro está sistemáticamente relacionado con la adaptación y las competencias académicas de los hijos. Este estudio pretende investigar la relación entre el informe de los padres sobre el apego ansioso y evitativo y el informe de sus hijos sobre la ansiedad rasgo y la autoeficacia académica en matemáticas y literatura turca. Madres (N=1539) y padres (N=1436) de cuatro ciudades en Turquía completaron por separado medidas de orientaciones de apego y sus hijos (N=1877) que frecuentan la 4ª y la 5ª clase completaron medidas de ansiedad rasgo y autoconcepto académico en matemáticas y literatura turca en su escuela. El análisis regresivo ha mostrado que el apego ansioso de las madres predecía la ansiedad rasgo de los niños, y el apego evitativo predecía la ansiedad de las niñas. Cuando se trata de la autoeficacia académica, el apego evitativo de las madres predecía la autoeficacia académica de sus hijos, y el apego ansioso de los padres predecía la autoeficacia de sus hijas, tanto en matemáticas como en la literatura turca. Nuestros resultados confirman la importancia que tiene una relación romántica segura entre los cónyuges, no sólo para la satisfacción y felicidad en su relación, sino también para la adaptación emocional y la competencia académica de sus hijos.

Negara Indonesia adalah negara yang berdasarkan atas hukum, bukan negara yang berdasarkan kekuasaan belaka, sebagai konsekuensi dari tata hukum tersebut. apabila ada orang yang merasa hak keperdataannya dilanggar atau dirugikan maka ia dapat mengajukan gugatan pada pengadilan negeri yang berwenangng. Gugatan yang diajukan tersebut tidak terlepas dari pembuktian yung mempunyai peran yang sangat penting khususnya pada alat bukti teitulis baik alat bukti tertulis tersebut diakui keberadaannya sebagai alat bukti maupun alat bukti tertulis tersebut dibantah atau disangkal oleh salah satu pihak yang berperkara guna untuk mencapai vonis atau keputusan yang akan dijatuhkan pada akhir perkara nantinya.

Introduction and Aims: Colonoscopy is the gold standard for diagnosing colorectal cancer (CRC) however there is a miss rate for cancers of up to 7.9%, with significant variability in this figure from different populations (1–5). Patient, procedural, and biological risk factors are thought to have an impact on this miss rate (1, 2, 6–9). We are performing a population-based, state-wide study to determine the proportion of missed and interval CRC that occur 3–36 months after a colonoscopy in an Australian population, and assess the characteristics of these cancer. Method: All individuals with a diagnosis of CRC identified through the WA Cancer Registry between January 1st 2000 to December 31st 2011 in Western Australia (WA) were included in the study. The WA Data Linkage Unit (DLU) is a state-wide comprehensive health data linkage system that can connect health events in all WA individuals across all hospital types. Individuals with a diagnosis of inflammatory bowel disease (IBD), CRC before 2000 or with multiple CRC's between 2000 and 2011 were excluded. Individuals who had a colonoscopy 3–36 months prior to the cancer diagnosis were classed as having a possible missed or interval cancer. A review of all these colonoscopy records is being undertaken to determine if the cancer was missed at the index colonoscopy, or is an interval cancer. A cancer was classified as missed if there was a significant abnormality seen at colonoscopy or procedural issues documented on the colonoscopy report that may have resulted in the cancer or pre-cancerous lesion being missed at the colonoscopy. Interval cancers were cancers that developed after a colonoscopy that did not document an abnormality in the anatomical location where the cancer developed. Results: There were 13, 828 CRCs diagnosed in WA over the 12-year period. Of these, 660 individuals had a colonoscopy performed 3–36 months before the cancer diagnosis. Preliminary results, after review of colonoscopy records, are availabl

Background & aims: Efforts are directed at reaching the optimal composition of pediatric amino acids (AA) infusions. The goal was to demonstrate the safety and efficacy of a newly developed parenteral AA solution containing alanyl-glutamine (GLN-AA) compared to Standard-AA. Methods: This is a randomized (2:1), double-blind, multicentre clinical pilot trial. Infants after surgical interventions were allocated to receive GLN-AA or Standard-AA over a minimum of 5 days to maximum of 10 days. AA profiles in blood samples obtained at baseline, day 7, and end of treatment were compared to normal ranges. Data regarding safety, and efficacy were also collected. Results: Infants were comparable for (safety population) gestational age at birth (36 vs 38 weeks), birth weight (2460 vs 2955 g), and day of life during start intervention (1 vs 2 days). Plasma AA profiles in infants treated with GLN-AA (n = 13) were closer the normal ranges than those in infants treated with Standard-AA (n = 6). There were no clinical or statistical differences in adverse events, safety and efficacy parameters between both groups. Conclusion: This first-in-man study shows that GLN-AA is safe in infants after surgical interventions, and is well tolerated. Compared to reference values, GLN-AA better reflects the amino acid requirements of the infant.

Green fluorescent protein (GFP) offers efficient ways of visualizing promoter activity and protein localization in vivo, and many different variants are currently available to study bacterial cell biology. Which of these variants is best suited for a certain bacterial strain, goal, or experimental condition is not clear. Here, we have designed and constructed two "superfolder" GFPs with codon adaptation specifically for Bacillus subtilis and Streptococcus pneumoniae and have benchmarked them against five other previously available variants of GFP in B. subtilis, S. pneumoniae, and Lactococcus lactis, using promoter-gfp fusions. Surprisingly, the best-performing GFP under our experimental conditions in B. subtilis was the one codon optimized for S. pneumoniae and vice versa. The data and tools described in this study will be useful for cell biology studies in low-GC-rich Gram-positive bacteria.

Contains fulltext : 103095.pdf (Publisher’s version ) (Open Access)

In 2007, the International Agency for Research on Cancer classified shift work involving circadian disruption as probably carcinogenic to humans (group 2A), primarily based on experimental and epidemiologic evidence for breast cancer. In order to examine options for evidence-based preventive actions, 16 researchers in basic, epidemiological and applied sciences convened at a workshop in Copenhagen 26-27 October 2011. This paper summarizes the evidence from epidemiological and experimental studies and presents possible recommendations for prevention of the effects of night work on breast cancer. Among those studies that quantified duration of shift work, there were statistically significant elevations in risk only after about 20 years working night shift. It is unclear from these studies whether or not there is a modest but real elevated risk for shorter durations. Hence, restriction of the total number of years working night shift could be one future preventive recommendation for shift workers. The diurnal secretion of melatonin by the pineal gland with peak in secretory activity during the night is a good biochemical marker of the circadian rhythm. Disruption of the diurnal melatonin secretion pattern can be diminished by restricting the number of consecutive night shifts. Reddish light and reduced light intensity during work at night could potentially help diminish the inhibitory activity of light with strong intensity on the melatonin secretion, but further mechanistic insight is needed before definite recommendations can be made. Earlier or more intensive mammography screening among female night shift worker is not recommended because the harm benefit ratio in this age group may not be beneficial. Preventive effects of melatonin supplementation on breast cancer risk have not been clearly documented, but may be a promising avenue if a lack of side effects can be shown even after long-term ingestion. Women with previous or current breast cancer should be advised n, AuthorCount:14